During a woman's reproductive life, a delicate and complex interplay of hormones are timed and controlled by the hypothalamus. The hormones that participate in the feedback system regulating the menstrual cycle include estrogens and progesterone, the pituitary gonadotropins FSH (follicle stimulating hormone) and LH (luteinizing hormone), and gonadotropin-releasing hormone (GnRH) from the hypothalamus.
Manipulation of the hormonal balance is a recognized approach of contraception and of treatment of benign gynecological disorders. In particular, administration of a GnRH compound for contraception has been described (U.S. Pat. Nos. 5,340,584; 5,211,952). Typically, the GnRH compound is administered in a slow or controlled-release fashion for continuous suppression of ovarian estrogen and progesterone production. Estrogen, often a progestin, and sometimes an androgen, are “added-back” to ameliorate the effects of hormonal deficiency. The hormone add-backs are also often administered in a slow, controlled-release or time-release fashion to maintain a constant hormonal serum level.
Treatment of benign gynecological disorders by administration of a GnRH compound has also been described (U.S. Pat. Nos. 5,340,584; 5,340,585; 5,681,817). During a women's reproductive years, defined as the time between onset of menses (menarche) and the final episode of bleeding (menopause), that is a premenopausal woman, a variety of benign gynecological disorders can occur. Common benign gynecological disorders include, but are not limited to, premenstrual syndrome, endometriosis, uterine leiomyomata (uterine fibroids), and polycystic ovarian syndrome. As for contraceptive use, a GnRH compound is administered to suppress ovarian follicle development and sex steroid production, and for benign gynecologic disorders, to relieve or treat symptoms associated with the disorder.
A woman's endogenous level of estrogen is significantly reduced upon entering menopause or upon premature surgical menopause induced by removal of the ovaries. The amount of a woman's endogenous estrogen is typically reduced to less than about 10% to about 20% of premenopausal levels following natural or surgical menopause. This reduction of endogenous estrogen levels results in the loss of estrogen's health protective effects, particularly with respect to bone mineral density. Estrogen replacement therapy (ERT) is often utilized as a treatment to increase the level of estrogen in women having reduced levels of endogenous estrogen resulting from natural or surgical menopause. Supplemental estrogen is provided to the women in order to inhibit, ameliorate, or prevent diseases or conditions which result from the reduction of endogenous estrogen.
The administration of drugs by absorption through mucosae, such as the nasal mucosa or vaginal mucosa, has been of considerable interest in recent years. This route of drug delivery is an alternative to oral administration in cases where drugs are poorly absorbed or are extensively metabolized in the gastrointestinal tract or subjected to first-pass metabolism in the liver. In particular, nasal mucosa has the desirable properties of being highly vascular leading to rapid uptake and of avoidance of first-pass metabolism in the liver, since the venous system from the nose passes directly into the systemic circulatory system. The nasal mucosa also exhibits moderate permeability to water-soluble compounds, comparable to that of the ileum. The permeability of nasal mucosa is higher for most compounds than other mucosa, due in part to the difference in structure of the cells lining the body cavities.
Efficiency of delivery of drugs by an intra-nasal route is influenced by the degree and rapidity of enzymatic degradation, the nasal clearance rate, as well as the drug's permeability through the mucosa. The clearance rate is produced by the coordinated movement of cilia and is known to be highly dependent upon the prevailing physiological and pathological conditions. Thus, for many drugs administration intranasally is inefficient due to low uptake of the drug, hence low bioavailability.
Another potential problem associated with intranasal delivery is mucosal irritation. Irritation caused by the drug itself and/or by absorption or penetration promoters or enhancers often limits the success of nasal formulations. Chronic administration of irritating nasal formulations can cause necrosis, inflammation, exudation, removal of the epithelial monolayer or can lead to irreversible damage to the nasal mucosa.
Nasal formulations for delivery of female sex hormones have been described (see, for example, U.S. Pat. Nos. 4,596,795; 5,089,482). However, formulations comprised of an estrogenic compound and an androgenic compound such as testosterone that are therapeutically effective when delivered intranasally and that are sufficiently non-irritating to the nasal mucosa for commercial viability have not been described.